DESCRIPTION: (Applicant's Abstract) Effects on children from intrauterine exposure to methamphetamine (MA) have been the focus of concern because although taken less frequently than cocaine its popularity in smoked form has increased in several regions of the U.S. In humans, MA has not been linked to congenital malformations, but preliminary indications of neurotoxicity have been reported. During the last funding period, following developmental MA treatment, we found persistent augmented acoustic startle reflexes, reduced nucleus accumbens serotonin, and most unexpectedly, spatial learning deficits. The focus of this application is to extend these findings in order to: (1) test the specificity of the spatial learning deficits by comparing its effects to nonspatial (proximal cue) learning, (2) test for its effects on working memory, (3) determine its effects on spatial discrimination and compare that to nonspatial discrimination, (4) investigate cholinergic and noradrenergic pathways to the hippocampus in relation to the spatial learning effects, noradrenergic innervation in the amygdala in relation to the startle effects, and changes in NMDA receptors in the hippocampus as another possible correlate of spatial learning deficits, (5) resolve several technical issues related to: dose rate (4 vs. 2 injection schedules), internal dose (pharmacokinetics), inclusion of undernourished controls in neonatal studies, and fostering/crossfostering controls in prenatal studies. The learning/memory procedures will be conducted in a Morris water maze. The Porsolt swim test will be used to determine if MA offspring have altered stress responsiveness similar to that reported after prenatal cocaine treatment. Reactivity procedures will be conducted using basic and fear-potentiated acoustic startle. Four exposure periods (2 prenatal and 2 neonatal) were chosen to span distinct stages of brain development (analogous to first, second, and early third human trimester brain development). The results will define the specificity of MA's developmental effects on spatial learning and startle, and begin the search for neurochemical correlates of these functional changes. The findings may assist in understanding the long-term risks to children exposed in utero to MA.